Esterification of polyene acids



Patented Jan. 29, 1952 2,583,594 ESTER-IFICATION F POLYENE ACIDS Charles D. Robeson, Rochester, N. Y., assignor to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing. Application April 22, 1950, Serial No. 157,622

r 17 Claims. (Cl. 260-4103) Other objects will be apparent from the description and claims which follow.

These and other objects are attained by means of this invention which comprises esterifying an a,;9-unsa.turated polyene acid by reacting, in a ketone. the acid to be esterified with an alkyl halide in the presence of a metal carbonate. By compounds and particularl b the labilit of the unsaturated linkages. This fnany conve ntional mans of the esteuficatlon pltlocess l i g chemical processes when employed with such 10 thls invenpion alkyl esters o i 8 polyene compounds cause isomerization of at polxene ands are Prepared m good meld Wlthout 1 1; portion of the polyene to an undesirable substantial formation of fin-unsaturated isomers isomer by shifting of the u'nsatumnon f the thereof as normally occurs with conventional molecule. esterification processes as applied to such polyene It is accordingly an object of this invention to acid$- provide a method of esterifying polyene acids h p e embodying the invention is 111118- Without affecting the unsaturation thereof. trated by the following reaction:

It is a further object of the invention to pro This invention relates to the esterification of polyene acids and is particularly concerned with methods of esterifying a,p-unsaturated polyene acids.

The treatment of long-chain polyene com- 5 pounds such as c p-unsaturated polyene acids is complicated by the inherent instability of such vide a method of esterifying el-unsaturated :CH CO0H+R,X w R=CH-COOR polyene aclds without substantial formation of 0 Metal carbons n any-unsaturated isomeric esters. I

Another object of the invention is to provide an improved method of esterifying vitamin A acid.

Another object of the invention is to provide a method of preparing c d-unsaturated conjugated carotenoid polyene esters in good yield.

Another object of the invention is to prevent wherein R is an unsaturated hydrocarbon radical, R is an alkyl group and X is a halogen atom. The a s-unsaturated polyene radical remains unchanged during the reaction. This is in contrast to the course of a conventional acidcatalyzed esterification process wherein a subiii g gzt eigia ifi g of vitamin A acid dur stantial portion of the product obtained from an Another object of the invention is to provide a Ha-unsaturated acid is the fill-unsaturated commercially feasible method of esterifying vita- 11161 of compound min A acid without objectionable loss in yield To illustrate, the esterificaflon of vitamin A due to formation of fin-unsaturated isomeric. acid by the well-known acid-catalyzed esterificaesters. tion processes proceeds as follows:

a o o OH; on,

oH=oH-t=0H-cH=oH-c :=cHo 0 OH R'OH Acid catalyst III H O C on. on,

H10 CH:

The reaction product in such case consists of a mixture of the desired a, 3-unsaturated conjugated polyene ester (Compound IV) and a ,8 unsaturated conjugated isomer (Compound V) of the desired compound. 1

In the process embodying this invention, the esterification of vitamin A acid or other carotenoid polyene acids such as B-ionylidene acetic acid or similar tip-unsaturated polyene acids gives substantially complete yields of the desired a e-unsaturated alkyl ester (Compound IV) according to the following reaction:

CHa

The esterification reaction embodying the invention can be carried out to produce any desired alkyl ester by choice of a suitable alkyl halide. to react with the tub-unsaturated polyene acid being esterifled including alkyl chlorides, bromides, iodidesand fluorides, and aryl-substituted alkyl halides such as benzyl halides. The 'alkyl iodides are preferred because of their superior reactivity. In some cases when an alkyl chlo- Any alkyl halide can be employed included in the reaction mixture although other dissociable iodides can be employed as the source of iodide ions. Allyl bromide can be satisfactorily employed alone, whereas an iodide is pref erably employed in conjunction'with ethyl bromide. When an alkyl iodide such as methyl' or ethyl iodide is employed, the course of the reactionfis notsubstantially affected by the presence'or absence of an inorganic iodide.

The e'steiification reaction embodying the invention is carried outwith the reactants in solution in aketone and in the presence of a metal carbonate. .Dialkylke'tones are desirably employed and particularly efficacious results are obained by eficcting the reaction in methyl ethyl ketone. Any metal carbonate can be employed which is effective to react with the polyene acid to form a metali'soap. Alkaline metal carbonates including alkali-metal and alkaline earth carbonates arapreierred with the alkali-metal carbonates such as. sodium and potassium carbonates being desirably employed. Other metal carbonates which are entirely suitable include calcium" carbonate and strontium carbonate, and these and other metal carbonates su h as .cupr carbonate can be employed in ccnjunction with such ketones as diethyl ketone, methyl ethyl ketone. acetone, methyl isobutyl ketone, cyclohexanone and the like. W

on; acid, and the like; and similar a,/8-unsatl1- rated. polyene acids.

The process embodying the invention further serves as a ready means for separating the ,5- unsaturated polyene mono-acids employed in practicing this invention from a,;3-unsaturated polyene diacids, since such diacids'do not esterify when subjected to the esterification process of the invention. Various a,;8-unsaturated monoaclds are desirably prepared by partial decarboxylation of the corresponding diacid. In such cases, the onoacid product is usually contaminated with undecarboxylated diacid and it is desirable to effect separation of the mixture. The process of this invention provides a ready means of effecting such separation because, unlike acidcatalyzed esterification processes, the process embodying this invention esterifies only the monoacid, to the substantial exclusion of the diacid. The unesterified diacid can thereafter' be sep arated from the monoacid ester by washing the diacid out with aqueous alkali or by other wellknown methods of separating acids and esters.

Thus, vitamin A diacids can be prepared by condensing fi-ionylidene acetaldehyde with a 6- methyl glutaconate diester or an isopropylidene malonate diester in the presence of a basic con densation catalyst, followed by saponification to form the 'diacid. These diacids are then decar boxylated to vitamin A acid by heating with a tertiary amine such as pyridine and a copperbearing material such as copper or a copper salt. The resulting vitamin A acid is usually contaminated with vitamin A diacid; By subjecting the product to the process embodying this invention, the vitamin A acid is esterified without isomerization and the diacid remains unesterifled and is readily removed by alkali washing.

The process of the invention is equally applicable for separating any of the other afl-unsaturated polyene acids from admixture with diacids in similar fashion.

Certain preferred embodiments of the'invention are illustrated by the following examples.

Example 1 A 0.5 g. portion of vitamin A acid was dissolved in 5 cc. of methyl ethyl ketone. To this solution was added 1.25 g. of ethyl bromide, 0.5 g. of potassium carbonate, and 0.005 g. of sodium iodide. The resulting reaction mixture was refluxed for 2 hours at 87-89 C., cooled, diluted with cc. of water and extracted with ether. The ether extract Was washed successively with 0.5 N. potassium hydroxide solution and with water, dried over sodium sulfate and the ether removed by evaporation. The ethyl ester of vitamin A acid was recovered in 100% yield and had Similar results were obtained with other carbonates such as cupric carbonate and sodium carbonate, and other ketones such as acetone and methyl isobutyl ketone.

Ezcample 2 A solution was prepared by dissolving in 250 cc. of methyl ethyl ketone, 53 g. of 3,7,11,15-tetramethy1-2,4,6,8,10,14-hexadecaeneoic acid E;Z-,,, (310 m )=552 Example 3 The allyl ester 01' vitamin A acid was prepared by mixing together 0.5 g. of vitamin A acid, 5 cc. of methyl ethyl ketone, 0.2 g. of potassium carbonate, 1.39 g. of allyl bromide and 0.005 g. of sodium iodide, and refluxing the resulting mixture for 2 hours on a steam bath. The reaction mixture was worked up in the usual way to give 0.545 g. of vitamin A acid allyl ester having Emm mt =1125 a yield of 97.5%,

Example 4 The benzyl ester of vitamin A acid was prepared as iollows. A 0.5 g. portion of vitamin A acid was dissolved in 5 cc. of methyl ethyl ketone, and to this solution was added 0.2 g. of sodium carbonate, 1.4 g. of benzyl chloride and 0.005 g. of sodium iodide. The reaction mixture was refluxed for 2 hours at 87-89 C., cooled, diluted with 50 cc. of water and extracted with ether. The ether extract was dried and the ether re moved by evaporation to give 1.11 g. of the crude benzyl ester of vitamin A acid having E}'f,,, (360 my) 405 Example 5 Fifteen grams of p-ionylidene acetic acid were dissolved in 100 cc. of methyl ethyl ketone, and 50 cc. of methyl iodide and 15 g. of potassium carbonate were added to the solution. The mixture was refluxed for 2 hours, an additional cc. of methyl iodide added, and reflux was continued for one hour. The reaction mixture was filtered, ether was added to the filtrate, and the etherfiltrate mixture was washed successively with water, with 0.5 N. aqueous potassium carbonate and again with water. The ether layer was thereafter separated and the ether removed by evaporation to give 14.7 g. of the methyl ester of B-ionylidene acetic acid as a pale yellow oil, a yield of 100%.

Example 6 The process embodying the invention is applicable for separating mixtures of a monoacid and a diacid. Thus, for example, p-ionylidene acetaldehyde and a diester of p-methyl glutaconic acid are condensed in the presence of a basic condensation catalyst such as potassium. hydroxide and the condensation product saponified to the diacid, y-carboxy vitamin A acid, by refluxing with additional potassium hydroxide. This diacid is then heated in the presence oi a tertiary amine, such as pyridine, and a copper-bearing compound, such as copper powder or copper acetate, to give vitamin A acid contaminated with undecarboxylated 'y-carboxy vitamin A acid.

The separation of vitamin A acid from unchanged diacid is effected according to the following procedure. A 30.1 g. portion of a methyl ethyl ketone solution of crude vitamin A acid from the decarboxylation was mixed with 15 cc. of methyl iodide and 5.0 g. of potassium carbonate. The solution empicyed contained 3.58 g. of vitamin A acid having and a small percentage 01' contaminating diacid. The resulting mixture was refluxed on a steam bath for 2 hours, diluted with water and extracted The aqueous layer was acidified with 10% hydrochloric acid, extracted with ether and the ether removed by evaporation to give 0.25 g. of y-carboxy vitamin A acid having an acid value of 2'72 and The process embodying the invention is applicable for esterifying other c p-unsaturated polyene acids in good yield and without isomerization. Any of the alkyl esters, including aralkyl esters, can be prepared by use of an appropriate alkyl halide. Any metal carbonate capable of forming a metal soap with the acid being esterifled can be employed, including such carbonates as calcium carbonate and strontium carbonate. Other ketones such as methyl isobutyl ketone, acetone and the like can also be employed, although methyl ethyl ketone is preferred for optimum results.

While the invention has been described in considerable detail with reference to certain preferred embodiments, it will be understood that these and other variations and modifications can be effected without departing from the spirit and scope of the invention as described hereinabove and as defined in the appended claims.

What I claim is:

1. The method of esteriiying an aye-unsaturated polyene acid without affecting the unsaturation thereof which comprises reacting, in a ketone, an tip-unsaturated polyene monobasic organic acid and an alkyl halide in the presence of a metal carbonate.

2. The method of esterifying an c d-unsaturated polyene acid without aflecting the unsaturation thereof which comprises reacting, in a ketone, an cap-unsaturated polyene monobasic organic acid and an alkyl halide in the presence of a basic metal carbonate.

3. The method of esterifying an a, 3-unsaturated polyene acid without affecting the unsaturation thereof which comprises reacting, in a. ketone, an (mp-unsaturated polyene monobasic organic acid'and an-alkyl halide in the presence of an "alkali-metal carbonate.

4. The method of esterifying an lac-unsaturated polyene acid without affecting the unsaturation thereof which comprises reacting, in methyl ethyl ketone, an rip-unsaturated conjugated polyene monobasic organic acid and an alkyl halide in the presence of a metal carbonate.

' comprises reacting, in a ketone, a completely conjugated ace-unsaturated carotenoid polyene m'onobasic organic acid and'an alkyl halide in the 1 presence of a metal carbonate.

7. The method of esterifying a,,8-unsaturated conjugated vitamin A acid which comprises reacting, in a ketone, vitamin A acid and an alkyl halide in the presence of a-basic metal carbonate.

3. The methodof esterifying rip-unsaturated conjugated vitamin A acid which comprises reacting, in a dialkyl 'ketone, vitamin A acid and an alkyl halide in the presence of a basic metal carbonate.

9. The 'method of esterifying vitamin A acid which comprises reacting, in methyl ethyl ketone, vitamin A acid and an alkyl halide in the presence of a metal carbonate.

' 105The method of esteriiying vitamin A acid which comprises reacting, in a ketone, vitamin A acid and an alkyl halide in the presence of a metal carbonateand a dissociable iodide.

11. The method of esterifying vitamin A acid which comprises reacting, in methyl ethyl ketone, vitamin A acid and an alkyl halide in the presence'of an alkali-metal carbonate.

12. The method of esterifying vitamin A acid which comprises reacting, in methyl ethyl ketone, vitamin A acid and analkyl halide in the presence of an alkali-metal carbonate and an alkali-metal iodide.

13. The method of preferentially esterifying an c-unsaturated polyene acid in admixture with a diacid which comprises reacting, in a ketone, a mixture of an tip-unsaturated polyene monobasic organic acid and an a d-unsaturated polyene diacid with an alkyl halide in the presence of a metal carbonate and thereby esteriiying said e-unsaturated polyene acid without substantially esterifying said diacid.

14. The method of esterifying an afi-ullSatllrated polyene acid which comprises reacting, in a dialkyl ketone, an s-unsaturated polyene monobasic organic acid having said a e-unsaturation in conjugation with at least one other aliphatic unsaturated linkage, and an alkyl halide in the presence of a basic metal carbonate.

15. The method of esterifying an rip-unsaturated conjugated carotenoid polyene acid which comprises reacting, in a dialkyl ketone, an 01,5- unsaturated completely conjugated carotenoid polyene monobasic organic acid having said a,fi- -unsaturation in conjugation with at least one other aliphatic" unsaturated linkage, and an alkyl halide in the presence of a basic metal carbonate.

16. The method of separating an r p-unsaturated conjugated polyene monobasic organic acid from a,'fl-unsaturated polyene diacid which comprises reacting, in a ketone, a mixture of said acid and said diacid with an alkyl halide inthe presence of a metal carbonate and thereby preferentially esterifying said acid, and separating the resulting ester of said acid from the unesteri-' fled diacid.

17. The method of separating vitamin A acid from admixture with vitamin A diacid which comprises reacting, in a ketone, a mixture of vitamin A acid and vitamin A diacid with-an alkyl halide in the presence of a metal carbonate and thereby preferentially esterifying said vitamin A acid, and separating the resulting ester of said vitamin A acid from the unesterified vitamin A diacid. 7

CHARLES .D. ROBESON.

No references cited. 

1. THE METHOD OF ESTERIFYING AN A,B-UNSATURATED POLYENE ACID WITHOUT AFFECTING THE UNSATURATION THEREOF WHICH COMPRISES REACTING, IN A KETONE, AN A,B-UNSATURATED POLYENE MONOBASIC ORGANIC ACID AND AN ALKYL HALIDE IN THE PRESENCE OF A METAL CARBONATE. 